Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer's disease mouse model

被引:239
作者
Delekate, Andrea [1 ]
Fuechtemeier, Martina [2 ,3 ]
Schumacher, Toni [1 ]
Ulbrich, Cordula [1 ]
Foddis, Marco [2 ]
Petzold, Gabor C. [1 ,4 ]
机构
[1] German Ctr Neurodegenerat Dis DZNE, D-53175 Bonn, Germany
[2] Charite, Dept Expt Neurol, D-10117 Berlin, Germany
[3] German Ctr Neurodegenerat Dis DZNE, D-10117 Berlin, Germany
[4] Univ Hosp Bonn, Dept Neurol, D-53127 Bonn, Germany
关键词
A-BETA-PLAQUES; CALCIUM WAVES; AMYLOID-BETA; TRANSGENIC MICE; P2Y(1) RECEPTORS; BRAIN-INJURY; BLOOD-FLOW; NETWORKS; ATP; NEURONS;
D O I
10.1038/ncomms6422
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Astrocytic network alterations have been reported in Alzheimer's disease (AD), but the underlying pathways have remained undefined. Here we measure astrocytic calcium, cerebral blood flow and amyloid-beta plaques in vivo in a mouse model of AD using multiphoton microscopy. We find that astrocytic hyperactivity, consisting of single-cell transients and calcium waves, is most pronounced in reactive astrogliosis around plaques and is sometimes associated with local blood flow changes. We show that astroglial hyperactivity is reduced after P2 purinoreceptor blockade or nucleotide release through connexin hemichannels, but is augmented by increasing cortical ADP concentration. P2X receptor blockade has no effect, but inhibition of P2Y1 receptors, which are strongly expressed by reactive astrocytes surrounding plaques, completely normalizes astrocytic hyperactivity. Our data suggest that astroglial network dysfunction is mediated by purinergic signalling in reactive astrocytes, and that intervention aimed at P2Y1 receptors or hemichannel-mediated nucleotide release may help ameliorate network dysfunction in AD.
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页数:14
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